Summary The central focus of this proposal is to understand the role of the NAD-dependent deacetylase sirtuin-2 (Sirt2) in hepatocellular carcinoma (HCC). HCC is the most rapidly increasing cancer in the United States. Currently, the pathogenic mechanisms underlying HCC are not fully known. Understanding the molecular signaling pathways that drive or mediate the development of HCC is important for the identification of novel therapeutic targets for preventing or treating HCC. Sirt2 is involved in various aspects of biological processes, such as aging, metabolism and cancer. There is a growing interest in targeting Sirt2 as a promising therapeutic strategy. Therefore, it is important to comprehend the physiological functions of Sirt2. Sirt2 is generally believed to be a tumor suppressor. However, recent studies showed that Sirt2 protein is overexpressed in HCC and correlated with poor prognosis of HCC. Thus, the role of Sirt2 in HCC remains controversial. Studying the role of Sirt2 in hepatocarcinogenesis by in vivo models will reveal new insights into the molecular mechanisms of HCC. Such insights will also provide a molecular basis for targeting Sirt2 as a therapeutic strategy. In this project, by using gain- and loss-of-function strategies, we will study the role of Sirt2 in hepatocarcinogenesis in vivo. We have generated a new transposon vector to determine how overexpression Sirt2 affects hepatocarcinogenesis. In addition, we will use an inducible hepatocyte-specific Sirt2-knockout mouse model to further study how deletion of Sirt2 in hepatocytes affects c-MET/-catenin-driven HCC formation and progression.